Type 1 diabetes mellitus (T1DM) typically results from immune mediated destruction of pancreatic beta cells. Previous studies indicate that some patients retain the capacity for limited endogenous insulin production. AC2993 (synthetic exendin-4) has been shown in preclinical and in preliminary human studies to have several potentially beneficial antidiabetic actions, including recovery and neogenesis of pancreatic islets. Purpose of this protocol: We investigate whether pancreatic insulin production can be enhanced in patients with long-standing T1DM (more than 5 years) by administering synthetic exendin-4, with or without concomitant immunosuppression (daclizumab). To be eligible, patients must have evidence of some residual pancreatic insulin production as reflected by measurable circulating C-peptide (between 0.3 ng/ml and <1.2 ng/ml). All patients will receive synthetic exendin-4 in a crossover design; half will receive immunosuppression with daclizumab. We assess endogenous islet function with repeated arginine-stimulated C-peptide tests. The protocol will also monitor glycemia control, insulin requirements, and assays to quantitate anti-islet immune responses. Background information: Considerable evidence, albeit indirect, supports the proposed chronic "race" between the immune system mediated islet destruction and a counter beta cell regenerative process. For instance, it is now well accepted that the anti-islet immune response exists for months and even years prior to T1DM onset. This observation is most intriguing since the immune system typically destroys targets with great efficiency and speed (e.g., the immune response leading to organ allograft rejection). While the gradual beta cell destruction could be due to immune regulatory processes bridling the destructive immune response, the fact that serologic evidence, e.g., anti-glutamic acid decarboxylase (GAD) antibodies persist in many patients with T1DM years after disease onset, suggests some persistence of the target cells driving the immune response. Further, ample data in rodents document that islet cell turnover persists at a low but steady rate throughout life, so islet regeneration can and does occur. Indeed, while controversial, a number of recent studies have demonstrated that a variety of tissues thought to have lost regenerative capacity (e.g., myocytes and neurons) can, under certain circumstances, be induced to proliferate. In 1992, Eng et al reported the isolation and characterization of exendin-4, a novel peptide from lizard venom that displays 52% identity to mammalian glucagon-like peptide (GLP 1). Exendin-4 was subsequently shown to bind the GLP 1 receptor, stimulate glucose-dependent insulin secretion, and increase both cAMP accumulation and insulin gene expression in cultured islet cell lines in vitro. More recently it has been found that GLP 1 induced activation of the GLP 1 receptor resulted in beta cell growth and differentiation by inducing the expression of the homeodomain protein IDX 1 (also known as PDX-1 or IPF-1) and that GLP 1 may lead to differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Though there is a striking homology between lizard exendin-4 and mammalian GLP 1 (a product of posttranslational processing of the proglucagon gene), it was determined that both are distinct peptides encoded by different genes and that there is no human equivalent of exendin-4. So far, all metabolic effects of exendin-4 appear to be mediated via the GLP 1 receptor. Synthetic exendin-4 (exenatide or Byetta (trade name)) has recently been approved for treatment in patients with type 2 diabetes and require insulin. Protocol update: More than 800 patients have contacted the NIH patient recruitment center and have subsequently received a questionnaire of which 150 were returned. Seventy-two patients were invited, we screened 43 patients, 27 patients were rejected for clinical reasons, 14 patients are in active phases of the protocol and 3 patients have terminated their participation early. Eleven patients have started or completed the ?run-in? protocol phase during which their baseline C-peptide producing capacity is assessed over 4 months with three arginine stimulation tests while the patients' blood glucose is maintained as closely to normal as possible. Of these eleven patients, seven have started study period A (2 patients are randomized to exendin-4 with daclizumab, 2 patients are randomized to receive neither exendin-4 or daclizumab, 2 patient are receiving exendin-4 alone and 1 patient is receiving daclizumab alone). None of our patients has experienced a serious adverse event so far and we have only observed minor adverse events.